Apparatuses and methods are known for simulating the dissolution behavior of pharmaceutical products in the human digestive system and for obtaining information about this process. Conventional apparatuses for testing the dissolution behavior of dosages of pharmaceutical products have a dissolution unit with multiple dissolution vessels, in each of which is placed a test solution and a dosage of a pharmaceutical product to be tested, such as a tablet. After a tablet, for example, has been placed in the test solution in a dissolution vessel in which the conditions prevailing in the human digestive system are to be simulated, a stirring element in the test solution is rotated at a specified rate for a specified duration. An example of such a dissolution unit is shown in U.S. Pat. No. 5,589,649.
In order to track the progress of the dissolution behavior over time, samples of a respective test solution in which the dosage of the pharmaceutical product dissolves are taken or withdrawn from a respective dissolution vessel at certain time intervals and are conveyed to an analytical instrument. Systems are known for this process, which are commonly referred to as autosamplers or samplers, in order to automate various aspects of withdrawing samples from the test solution and conveying the samples that have been withdrawn or taken to an analytical instrument. In such systems, samples and other fluids are conveyed by pumps through tubing lines. Samplers are known which allow the testing of several dosages of a pharmaceutical process at the same time, in which samples of test solution with the dosage of the pharmaceutical product dissolving therein are withdrawn from each dissolution vessel a number of times. In prior art samplers, the withdrawn samples are delivered to collection receptacles, such as test tubes or vials, for temporary storage prior to analysis. The samplers may also automatically transfer samples from the collection receptacles to an analytical instrument at appropriate times for analysis.
Samplers typically have a rack that can hold a group of collection receptacles for keeping collected samples, and a head at which a set of lines terminates, the lines each being connected to a pump to serve a particular dissolution vessel. The head and the group of collection receptacles can be moved and positioned relative to one another so that a particular withdrawn sample can be delivered to a particular collection receptacle for storage. Prior art systems may also be designed to flush, wash, and purge the tubing lines, and to replace the test solution in which a dosage of the pharmaceutical product is dissolving that has been withdrawn from the dissolution vessels with fresh test solution, which is known as media replacement, and/or to return to the dissolution vessels a portion of the withdrawn test solution that is not delivered to the collection receptacles, which is known as media recycling.
In prior art samplers, the pumps for transporting fluids are implemented as tubing pumps or as piston pumps.
In a sampler with tubing pumps or peristaltic pumps, respective elastic tubing sections of the lines are mechanically deformed or compressed by means of a motor in such a manner that the medium to be transported is forced through the tubing section, and thus through the line. In this context, the transport can be bidirectional, which is to say that the medium can be transported along the line in both directions. The intake and delivery pressure of a tubing pump is very limited, however, and the metering precision depends strongly on the back pressure and the operating life or service life. Furthermore, the reliability of delivery decreases with increasing operating life or life time of a tubing pump, since the tubing sections that are peristaltically compressed can stick together, for example, and thus hamper the flow of fluid.
In some prior art samplers, piston/syringe pumps are used instead of tubing pumps, since they operate with greater precision and reliability than tubing pumps. With valves at the inlet and outlet, bidirectional fluid transport can also be achieved. A sampler with a pump unit that includes piston/syringe pumps is described in U.S. Pat. No. 6,948,389. The pump unit described in U.S. Pat. No. 6,948,389 has eight piston pumps, each with a piston that is movable in a cylindrical pump element. The lower ends of the pistons are secured to a flange which, when raised and lowered by a mechanism driven by a motor, moves the pistons upward and downward within the cylindrical pump elements.
Samplers with piston/syringe pumps are relatively complex in technical terms, and because of the relatively large dwell volume (which is likewise known from HPLC to those skilled in the art as the volume that must be pumped until the fresh medium at the outlet of the pump system has a content of approximately 72%), and because of the fact that the FIFO principle (i.e., “first in-first out”) cannot be implemented with such samplers, they are not well suited for media undergoing change, such as is the case for the change in concentration of the test solution with the dosage of the pharmaceutical product dissolving therein. Furthermore, when the piston moves within the cylindrical pump element, the friction of the piston seal on the inner surface of the cylindrical pump element, which is often made of glass, produces abraded particles, which get into the sample and can adversely affect the measurements, such as fluorescence detection, at the analytical instrument. Finally, the piston seals of piston/syringe pumps are subject to severe wear, so that they need to be serviced and replaced frequently.
The object of the present invention is thus to provide an improved sampler that does not exhibit the disadvantages described above.